Diabetic patients often suffer a variety of pathological complications such as visual impairment and neuropathy. Neuropathy can be disabling because of unremitting pain.
Diabetic retinopathy is one of the leading causes of new cases of adult blindness in the United States. Approximately 15 million people in the United States suffer with type 2 diabetes, and the prevalence of this disease, especially in the young obese, is increasing dramatically. Population-based epidemiological studies indicate that macular edema, the leakage of plasma proteins from capillaries onto the retina, is the most common form of vision threatening retinopathy in type 2 diabetes. Macular edema is under-recognized and can only be diagnosed through an examination by a trained eye care professional, optometrist or ophthalmologist. Leakage of protein from damaged retinal capillaries can cause progressive visual impairment and may be a precursor for a more serious vision-threatening form of diabetic retinopathy-proliferative retinopathy. Leakage from capillaries, diabetic macular edema, requiring therapeutic intervention with laser photocoagulation, is not easy to predict by any known method other than frequent opthalmologic examinations which may be costly, inconvenient, or even unavailable to patients residing in rural areas or a great distance from limited opthalmologic resources. The advent of a simple blood test which is predictive of an increased risk for diabetic macular edema, could help identify the high risk subset of diabetic patients needing more urgent referral to eye care professionals, for examination and treatments to prevent visual impairment.
A test for detecting endothelial cell autoantibodies has been previously described (Zimering, M B and Thakker-Varia, S. Increased fibroblast growth factor-like autoantibodies in serum from a subset of patients with cancer-associated hypercalcemia. Life Sciences, 71 (2002) 2939-2959).
Endothelial cell autoantibodies are highly prevalent in a wide range of autoimmune disorders, e.g. lupus, vasculitis. Our group published findings that endothelial cell inhibitory autoantibodies also occur in a subset of advanced cancer patients (Zimering, M B and Thakker-Varia, S. Increased fibroblast growth factor-like autoantibodies in serum from a subset of patients with cancer-associated hypercalcemia. Life Sciences, 71 (2002) 2939-2959).
Circulating autoantibodies which bind to endothelial cells have been recognized for some time in a number of autoimmune disorders. The occurrence of such antibodies has been implicated in a number of possible disease manifestations including proliferative diabetic retinopathy in type 1, autoimmune diabetes (Jones D B, Wallace R, Frier B M. Vascular cell antibodies in diabetic patients. Association with diabetic retinopathy. Diabetes Care. 1992, 15(4), p. 552-555). However, in the same small study of endothelial cell binding autoantibodies in type 2, adult-onset diabetes, the same authors found no correlation between such antibodies and retinopathy or the lack of diabetic retinopathy (23-26% of both kinds of patients had such circulating antibodies, Jones D B, Wallace R, Frier B M. Vascular cell antibodies in diabetic patients. Association with diabetic retinopathy. Diabetes Care. 1992, 15(4), p. 552-555). Two larger studies, the first involving 176 type 1 diabetic subjects (Wangel A G, Kontiainen S, Scheinin T, Schlenzka A, Wangel D, Mäenpää J. Anti-endothelial cell antibodies in insulin-dependent diabetes mellitus. Clin Exp Immunol 1992 88 (3) p. 410-413) and the second involving 777 diabetics (Petty R G, Pottinger B E, Greenwood R M, Pearson J D, Mahler R F. Diabetes is associated with a high incidence of endothelial-binding antibodies which do not correlate with retinopathy, von Willebrand factor, angiotensin-converting enzyme or C-reactive protein. Diabetes Res. 1991 July; 17(3):115-23) each found no correlation between endothelial antibodies retinopathy or other diabetic microvascular complications. For this reason, the possibility that endothelial cell autoantibodies might mediate diabetic macular edema in non-insulin dependent, non-autoimmune type 2 diabetes was not previously explored systemically, in any known published study.
In summary, previous published studies indicated a relationship between plasma endothelial cell binding antibodies and proliferative diabetic retinopathy in type 1, “auto-immune” diabetes (Jones et al., 1992, supra). No such relationship, however, was demonstrated for a more common form of retinal complication suffered by patients with type 2 diabetes, so-called macular edema. In fact, the data shown herein for type 2 diabetes differs from the conclusions reached by Jones et al., 1992 (supra) that endothelial cell binding autoantibodies do not correlate with retinopathy in type 2 diabetes.
The invention herein describes the novel application of detecting endothelial cell antibodies for the detection and monitoring of specific diabetic complications associated with diabetes, particularly visual impairment.